Protease cleavage of RNF20 facilitates coronavirus replication via stabilization of SREBP1.
Protease cleavage of RNF20 facilitates coronavirus replication via stabilization of SREBP1.
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DOI：
10.1073/pnas.2107108118
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发表时间：
2021-09-14
影响因子：
11.1
通讯作者：
Cheng G
中科院分区：
文献类型：
--
作者：
Zhang S;Wang J;Cheng G
SARS-CoV-2具有用于病毒多蛋白加工的主要蛋白酶。但是很少有研究关注这种蛋白酶的宿主因子目标。在这里，我们筛选了近300个干扰素刺激基因（ISGs），发现RNF20被3Clpro切割，从而阻止RNF20/RNF40复合物介导的SREBP1降解，从而促进SARS-CoV-2复制。我们的研究将鼓励人们不仅针对冠状病毒蛋白酶，还针对宿主因子开发药物。COVID-19是由严重急性呼吸道冠状病毒2 （SARS-CoV-2）引起的，对全球公共卫生构成严重威胁。由NSP5编码的病毒主蛋白酶Mpro（也称为3Clpro）是病毒复制所必需的酶。然而，很少有宿主蛋白被实验证实为3Clpro的靶标。本研究基于NetCorona预测方法，通过对300个干扰素刺激基因（ISGs）的生物信息学分析，我们发现RNF20 （Ring Finger Protein 20）是3Clpro的新靶点。我们还提供了证据表明，3Clpro，而不是没有催化活性的突变体3ClproC145A，在物种间切割RNF20的保守Gln521，随后阻止SREBP1进行RNF20介导的降解并促进SARS-CoV-2复制。我们发现，RNA干扰（RNAi）介导的RNF20或RNF40的缺失均可显著增强病毒复制，这表明RNF20/RNF40复合物对SARS-CoV-2具有抗病毒作用。SREBP1参与SARS-CoV-2感染的证据是，SREBP1敲低和抑制剂AM580的细胞中病毒复制减少。综上所述，我们的研究结果揭示了RNF20是SARS-CoV-2主要蛋白酶的新宿主靶点，并表明3Clpro抑制剂可能不仅通过阻断病毒多蛋白切割，而且通过增强宿主抗病毒反应来治疗COVID-19。
SARS-CoV-2 has a main protease for viral polyprotein processing. But too few studies addressed this protease’s target of host factors. Here, we screen nearly 300 interferon-stimulated genes (ISGs) and identify that RNF20 is cleaved by 3Clpro, which prevents SREBP1 degradation mediated by RNF20/RNF40 complex, thus promoting SARS-CoV-2 replication. Our study will encourage people to develop drugs against not only coronavirus protease but also host factors. COVID-19, caused by severe acute respiratory coronavirus 2 (SARS-CoV-2), has presented a serious risk to global public health. The viral main protease Mpro (also called 3Clpro) encoded by NSP5 is an enzyme essential for viral replication. However, very few host proteins have been experimentally validated as targets of 3Clpro. Here, through bioinformatics analysis of 300 interferon stimulatory genes (ISGs) based on the prediction method NetCorona, we identify RNF20 (Ring Finger Protein 20) as a novel target of 3Clpro. We have also provided evidence that 3Clpro, but not the mutant 3ClproC145A without catalytic activity, cleaves RNF20 at a conserved Gln521 across species, which subsequently prevents SREBP1 from RNF20-mediated degradation and promotes SARS-CoV-2 replication. We show that RNA interference (RNAi)-mediated depletion of either RNF20 or RNF40 significantly enhances viral replication, indicating the antiviral role of RNF20/RNF40 complex against SARS-CoV-2. The involvement of SREBP1 in SARS-CoV-2 infection is evidenced by a decrease of viral replication in the cells with SREBP1 knockdown and inhibitor AM580. Taken together, our findings reveal RNF20 as a novel host target for SARS-CoV-2 main protease and indicate that 3Clpro inhibitors may treat COVID-19 through not only blocking viral polyprotein cleavage but also enhancing host antiviral response.
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DOI：
10.1016/s2213-2600(20)30579-8
发表时间：
2021-04
期刊：
The Lancet. Respiratory medicine
影响因子：
--
作者：
Navaratnam AV;Gray WK;Day J;Wendon J;Briggs TWR
通讯作者：
Briggs TWR
干扰素刺激的基因及其抗病毒效应子功能。
影响因子：
5.9
作者：
Schoggins, John W.;Rice, Charles M.
通讯作者：
Rice, Charles M.
DOI：
10.1073/pnas.1404271111
发表时间：
2014-07-22
影响因子：
11.1
作者：
Gold, Elizabeth S.;Diercks, Alan H.;Aderem, Alan
通讯作者：
Aderem, Alan
影响因子：
30.3
作者：
Hoffmann HH;Sánchez-Rivera FJ;Schneider WM;Luna JM;Soto-Feliciano YM;Ashbrook AW;Le Pen J;Leal AA;Ricardo-Lax I;Michailidis E;Hao Y;Stenzel AF;Peace A;Zuber J;Allis CD;Lowe SW;MacDonald MR;Poirier JT;Rice CM
通讯作者：
Rice CM
影响因子：
5.4
作者：
Kopecky-Bromberg, Sarah A.;Martinez-Sobrido, Luis;Palese, Peter
通讯作者：
Palese, Peter